Potent peptidic fusion inhibitors of influenza virus

• Published in: Science (American Association for the Advancement of Science) Vol. 358; no. 6362; pp. 496 - 502
• Main Authors: Kadam, Rameshwar U., Juraszek, Jarek, Brandenburg, Boerries, Buyck, Christophe, Schepens, Wim B. G., Kesteleyn, Bart, Stoops, Bart, Vreeken, Rob J., Vermond, Jan, Goutier, Wouter, Tang, Chan, Vogels, Ronald, Friesen, Robert H. E., Goudsmit, Jaap, van Dongen, Maria J. P., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 27.10.2017; The American Association for the Advancement of Science; AAAS
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antibodies; Antibodies, Neutralizing - chemistry; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Biological properties; Complementarity; Complementarity Determining Regions - chemistry; Complementarity-determining region; Crystallography, X-Ray; Disease resistance; Drug Design; Drugs; Epitopes; Glycoproteins; Hemagglutinins; Humans; Immunoglobulins; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H5N1 Subtype - drug effects; Inhibitors; Life cycle engineering; Life cycles; Male; Membrane fusion; Mice; Mice, Inbred BALB C; Neutralization; Neutralizing; Pandemics; Peptide inhibitors; Peptides; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; pH effects; Protein Conformation; RESEARCH ARTICLE; Strains (organisms); Structural analysis; Virus Internalization - drug effects; Viruses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aan0516

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.